Glycerol Phenylbutyrate Research Articles

7494 Glycerol Phenylbutyrate Treatment of Two Patients with Monocarboxylate Transporter 8 Deficiency

Abstract Disclosure: A. Zung: None. N. Sonntag: None. U. Schweizer: None. E. Banne: None. D. Braun: None. Context: Monocarboxylate transporter 8 (MCT8) deficiency is a rare genetic disease that leads to severe global developmental delay. MCT8 facilitates thyroid hormone (TH) transport across the cell membrane, and the serum TH profile is characterized by high T3 and low T4 levels. Currently, the two thyromimetic agents 3,5-diiodothyropropionic acid (DITPA) and triiodothyroacetic acid (TRIAC) have been evaluated in the treatment of these patients, as they both partially restore intracellular TH action independent of MCT8. Recent studies have shown that the chemical chaperone sodium phenylbutyrate (NaPB) restored mutant MCT8 function and increased TH content in patient-derived induced pluripotent stem cells, making it a potential treatment for MCT8 deficiency. Objective: We aimed to assess the efficacy and safety of glycerol phenylbutyrate (GPB) in MCT8 deficiency. Methods: We treated two monozygotic twins aged 14.5 years with MCT8 deficiency due to P321L mutation with escalating doses of GPB over 13 months. We recorded TH, serum markers of peripheral hyperthyroidism, vital signs, anthropometric measurements and neurocognitive functions by several neurodevelopment validated tests. Resting metabolic rate (RMR) was measured by indirect calorimetry. Serum metabolites of GPB were monitored as a safety measure. In-vitro effects of NaPB were evaluated in MDCK1 cells stably expressing the MCT8P32[1]L mutation. Results: NaPB restored mutant MCT8 expression in MDCK1 cells and increased T3 transport into cells carrying the P321L mutation. GPB treatment yielded a dose-dependent decrease in FT3 and an increase in FT4 serum levels. The patients showed an elevation in cholesterol levels in parallel with GPB dose, but sex-hormone binding protein (SHBG), another marker of peripheral hyperthyroidism was not affected. The patients showed a significant weight gain simultaneously with a reduction in RMR. Only minor neuro-cognitive improvement was observed, mainly in hyperreflexia score, slight improvement in gross motor functions and a mild progression in cognitive functions. Serum metabolites of GPB did not exceed the toxic range but elevated liver transaminases restricted the dose intensification of GPB. Conclusions: In the first report of GPB treatment in MCT8 deficiency patients we found an improvement in TH profile and body-mass index (BMI). The reduction in T3 levels could contribute to the remarkable increase in BMI-SDS, since various aspects of peripheral hyperthyroidism in MCT8 deficiency, including poor weight gain, were attributed to elevated T3. The limited effects of GPB treatment on cognitive and motor functions can derive from the advanced age of the patients at the time of the intervention. Presentation: 6/2/2024

Glycerol Phenylbutyrate Treatment of 2 Patients With Monocarboxylate Transporter 8 Deficiency.

Monocarboxylate transporter 8 (MCT8) deficiency is a rare genetic disease that leads to severe global developmental delay. MCT8 facilitates thyroid hormone (TH) transport across the cell membrane, and the serum TH profile is characterized by high T3 and low T4 levels. Recent studies have shown that the chemical chaperone sodium phenylbutyrate (NaPB) restored mutant MCT8 function and increased TH content in patient-derived induced pluripotent stem cells, making it a potential treatment for MCT8 deficiency. We aimed to assess the efficacy and safety of glycerol phenylbutyrate (GPB) in MCT8 deficiency. We treated 2 monozygotic twins aged 14.5 years with MCT8 deficiency due to P321L mutation with escalating doses of GPB over 13 months. We recorded TH, vital signs, anthropometric measurements, and neurocognitive functions. Resting metabolic rate (RMR) was measured by indirect calorimetry. Serum metabolites of GPB were monitored as a safety measure. In vitro effects of NaPB were evaluated in MDCK1 cells stably expressing the MCT8P321L mutation. The effects of GPB were compared to the effects of DITPA and TRIAC, thyromimetic medications that the patients had received in the past. NaPB restored mutant MCT8 expression in MDCK1 cells and increased T3 transport into cells carrying the P321L mutation. GPB treatment reduced high T3 and increased low T4 levels. The patients showed a significant weight gain simultaneously with a reduction in RMR. Only minor neurocognitive improvement was observed, in hyperreflexia score and in cognitive functions. Serum metabolites did not exceed the toxic range, but elevated liver transaminases were observed. In the first report of GPB treatment in MCT8 deficiency we found an improvement in TH profile and body mass index, with minor neurodevelopmental changes.

An Alternative Pathway for the Synthesis of Glycerol Phenylbutyrate

AbstractHyperammonemia is a life‐threatening condition which can affect patients at any age. In pediatric patients, hyperammonemia can be caused by various acquired or inherited disorders such as urea cycle deficiencies or organic acidemias. Glycerol phenylbutyrate (GPB) is an orphan drug used in the treatment of hyperammonemia. GPB is a triglyceride composed of three phenylbutyric acid (PBA) molecules esterified to a glycerol molecule, which is synthesized through the acyl chloride route using thionyl chloride as an acylating agent. In this work we have developed an alternative synthesis method to obtain GPB directly under ambient conditions and avoiding the use of chlorinated solvents. Moreover, the use of carbodiimides as coupling agents, instead of thionyl chloride, allowed the conversion to the GPB in higher yields and with higher purity, without the need for column purification. We present a methodology that allows the production of GPB in a simple, efficient and environmentally and human health friendly way.

An Expedient Undergraduate Synthesis of Glycerol Phenylbutyrate, One of the Most Expensive Medications in the United States

An Expedient Undergraduate Synthesis of Glycerol Phenylbutyrate, One of the Most Expensive Medications in the United States

Treatment and management for children with urea cycle disorder in chronic stage.

Urea cycle disorder (UCD) is a group of inherited metabolic diseases with high disability or fatality rate, which need long-term drug treatment and diet management. Except those with Citrin deficiency or liver transplantation, all pediatric patients require lifelong low protein diet with safe levels of protein intake and adequate energy and lipids supply for their corresponding age; supplementing essential amino acids and protein-free milk are also needed if necessary. The drugs for long-term use include nitrogen scavengers (sodium benzoate, sodium phenylbutyrate, glycerol phenylbutyrate), urea cycle activation/substrate supplementation agents (N-carbamylglutamate, arginine, citrulline), etc. Liver transplantation is recommended for pediatric patients not responding to standard diet and drug treatment, and those with severe progressive liver disease and/or recurrent metabolic decompensations. Gene therapy, stem cell therapy, enzyme therapy and other novel technologies may offer options for treatment in UCD patients. The regular biochemical assessments like blood ammonia, liver function and plasma amino acid profile are needed, and physical growth, intellectual development, nutritional intake should be also evaluated for adjusting treatment in time.

Current Management of Hepatic Encephalopathy: A Review Article

Hepatic encephalopathy, a neuropsychiatric syndrome stemming from liver failure, manifests in acute and chronic cases. The prevailing cause behind its development involves the neurotoxicity resulting from elevated ammonia levels in the brain, which can occur due to increased ammonia production or impaired ammonia excretion. The main objective in treating hepatic encephalopathy is to decrease ammonia levels. The detoxification of ammonia in this condition is regulated by two enzymes: glutaminase and glutamine synthetase. Numerous drugs, such as lactulose, rifaximin, BCAA, LOLA, glycerol phenylbutyrate, and zinc, have been utilized to treat hepatic encephalopathy. In terms of future research, experimental treatment options like fecal microbiota transplant, probiotics, bromocriptine, minocycline, indomethacin, ibuprofen, and flumazenil warrant investigation. Furthermore, albumin infusions have been shown to enhance cognitive function and improve the psychosocial quality of life, possibly by alleviating endothelial dysfunction in patients with minimal hepatic encephalopathy or previous episodes of hepatic encephalopathy. This review article offers a comprehensive overview of the current management strategies for hepatic encephalopathy.

Monitoring the treatment of urea cycle disorders using phenylbutyrate metabolite analyses: Still many lessons to learn

Medications that elicit an alternate pathway for nitrogen excretion such as oral sodium phenylbutyrate (NaPBA) and glycerol phenylbutyrate (GPB) and intravenous sodium phenylacetate (NaPAA) are important for the management of urea cycle disorders (UCDs). Plasma concentrations of their primary metabolite, phenylacetate (PAA), as well as the ratio of PAA to phenylacetylglutamine (PAGN) are useful for guiding dosing and detecting toxicity. However, the frequency of toxic elevations of metabolites and associated clinical covariates is relatively unknown. A retrospective analysis was conducted on 1255 plasma phenylbutyrate metabolite measurements from 387 individuals. An additional analysis was also conducted on a subset of 68 individuals in whom detailed clinical information was available. In the course of these analyses, abnormally elevated plasma PAA and PAA:PAGN were identified in 39 individuals (4.15% of samples) and 42 individuals (4.30% of samples), respectively. Abnormally elevated PAA and PAA:PAGN values were more likely to occur in younger individuals and associate positively with dose of NAPBA and negatively with plasma glutamine and glycine levels. These results demonstrate that during routine clinical management, the majority of patients have PAA levels that are deemed safe. As age is negatively associated with PAA levels however, children undergoing treatment with NaPBA may need close monitoring of their phenylbutyrate metabolite levels.

Clearance and production of ammonia quantified in humans by constant ammonia infusion – the effects of cirrhosis and ammonia-targeting treatments

Hyperammonaemia is a key pathological feature of liver disease and the primary driver of hepatic encephalopathy (HE). However, the relative roles of increased ammonia production and reduced clearance are poorly understood as is the action of ammonia-targeting drugs for HE. We aimed to quantify whole-body ammonia metabolism in healthy persons and patients with cirrhosis and to validate our method by examining the effects of glycerol phenylbutyrate and lactulose+ rifaximin treatment. Ten healthy men and ten male patients with cirrhosis were investigated by 90-minute constant ammonia infusion to achieve steady-state plasma ammonia. Whole-body ammonia clearance was calculated as infusion rate divided by steady-state concentration increase and ammonia production was calculated as clearance multiplied by baseline ammonia concentration. Participants were re-investigated after the ammonia-targeting interventions. In healthy persons, ammonia clearance was 3.5 (3.1-3.9) L/min and ammonia production was 49 (35-63) μmol/min. Phenylbutyrate increased clearance by 11% (4-19%, p= 0.009). In patients with cirrhosis, ammonia clearance was 20% lower at 2.7 (2.1-3.3) L/min (p= 0.02) and production was nearly threefold higher at 131 (102-159) μmol/min (p <0.0001). Lactulose+ rifaximin reduced production by 20% (2-37%, p= 0.03). The infusion was generally well-tolerated apart from in one hyperammonaemic patient, with cirrhosis and possible bleeding unrelated to the infusion, who developed clinical HE that reverted when infusion was discontinued. Whole-body ammonia clearance and production may be measured separately using the described technique. This technique identified a lower clearance and a higher production of ammonia in patients with cirrhosis, and showed that phenylbutyrate increases clearance, whereas lactulose+ rifaximin reduces production. High blood ammonia plays a key role in cirrhosis-related brain dysfunction. However, the relative roles of reduced ammonia clearance and increased ammonia production are poorly understood as is the action of ammonia-targeting treatments. This study presents a relatively simple test to measure ammonia metabolism. By using this test, it was possible to show that patients with cirrhosis exhibit decreased ammonia clearance and increased ammonia production compared to healthy persons, and to quantify the unique effects of different ammonia-targeting treatments. The test described herein may be used to examine a range of questions related to normal physiology, pathophysiology and the mechanisms of action of ammonia-targeting treatments. ClinicalTrials.gov (1-16-02-297-20).

Taste-masked formulation of sodium phenylbutyrate (ACER-001) for the treatment of urea cycle disorders

Urea cycle disorders (UCDs) are a group of rare inherited metabolic diseases caused by a deficiency of one of the enzymes or transporters that constitute the urea cycle. Defects in these enzymes lead to acute accumulation (hyperammonemic crises, HAC) or chronically elevated levels (hyperammonemia) of ammonia in the blood and/or various tissues including the brain, which can cause persistent neurological deficits, irreversible brain damage, coma, and death. Ongoing treatment of UCDs include the use of nitrogen-scavenging agents, such as sodium phenylbutyrate (salt of 4-phenylbutyric acid; NaPBA) or glycerol phenylbutyrate (GPB). These treatments provide an alternative pathway for nitrogen disposal through the urinary excretion of phenylacetylglutamine. ACER-001 is a novel formulation of NaPBA with polymer coated pellets in suspension, which is designed to briefly mask the unpleasant bitter taste of NaPBA and is being developed as a treatment option for patients with UCDs. Four Phase 1 studies were conducted to characterize the bioavailability (BA) and/or bioequivalence (BE) of ACER-001 (in healthy volunteers) and taste assessment relative to NaPBA powder (in taste panelists). ACER-001 was shown to be bioequivalent to NaPBA powder under both fed and fasting conditions. Lower systemic exposure of phenylacetate (PAA) and phenylbutyrate (PBA) was observed when ACER-001 was administered with a high-fat meal relative to a fasting state suggesting that the lower doses of PBA administered under fasting conditions may yield similar efficacy with potentially fewer dose dependent adverse effects relative to higher doses with a meal. ACER-001 appeared to be adequately taste-masked, staying below the aversive taste threshold for the first 3min after the formulation was prepared and remaining palatable when taken within 5min.

Switching to Glycerol Phenylbutyrate in 48 Patients with Urea Cycle Disorders: Clinical Experience in Spain.

Background and objectives: Glycerol phenylbutyrate (GPB) has demonstrated safety and efficacy in patients with urea cycle disorders (UCDs) by means of its clinical trial program, but there are limited data in clinical practice. In order to analyze the efficacy and safety of GPB in clinical practice, here we present a national Spanish experience after direct switching from another nitrogen scavenger to GPB. Methods: This observational, retrospective, multicenter study was performed in 48 UCD patients (age 11.7 ± 8.2 years) switching to GPB in 13 centers from nine Spanish regions. Clinical, biochemical, and nutritional data were collected at three different times: prior to GPB introduction, at first follow-up assessment, and after one year of GPB treatment. Number of related adverse effects and hyperammonemic crisis 12 months before and after GPB introduction were recorded. Results: GPB was administered at a 247.8 ± 102.1 mg/kg/day dose, compared to 262.6 ± 126.1 mg/kg/day of previous scavenger (46/48 Na-phenylbutyrate). At first follow-up (79 ± 59 days), a statistically significant reduction in ammonia (from 40.2 ± 17.3 to 32.6 ± 13.9 μmol/L, p < 0.001) and glutamine levels (from 791.4 ± 289.8 to 648.6 ± 247.41 μmol/L, p < 0.001) was observed. After one year of GPB treatment (411 ± 92 days), we observed an improved metabolic control (maintenance of ammonia and glutamine reduction, with improved branched chain amino acids profile), and a reduction in hyperammonemic crisis rate (from 0.3 ± 0.7 to less than 0.1 ± 0.3 crisis/patients/year, p = 0.02) and related adverse effects (RAE, from 0.5 to less than 0.1 RAEs/patients/year p < 0.001). Conclusions: This study demonstrates the safety of direct switching from other nitrogen scavengers to GPB in clinical practice, which improves efficacy, metabolic control, and RAE compared to previous treatments.

Considerations for prenatal and postpartum management of a female patient with ornithine transcarbamylase deficiency

We report on pregnancy management and outcomes in a 27-year-old female patient with ornithine transcarbamylase (OTC) deficiency, the most common inherited enzyme deficiency in the urea cycle. Our patient was diagnosed during childhood after hyperammonemia associated with surgery and steroid treatment and was well-controlled with nitrogen scavenger treatment, low-protein diet, and L-citrulline supplementation. OTC gene sequencing identified a variant of unknown significance that has more recently been classified as likely pathogenic. Women with OTC deficiency are at increased risk of hyperammonemia during pregnancy and the postpartum period, therefore monthly follow up and laboratory assessments are critical in management decision making. Our patient was maintained on glycerol phenylbutyrate, L-citrulline and essential amino acid supplements, along with restricted protein intake during pregnancy. A multidisciplinary approach with the obstetrics, prenatal genetics, high risk obstetric, and anesthesia teams was also necessary for optimal management during pregnancy, throughout labor and delivery, and during the postpartum period. After successful childbirth and discharge, our patient experienced a hyperammonemic crisis related to poor enteral nutrition, and acute management protocols were implemented to stabilize her. For her newborn son, acute hyperammonemia protocols were on standby, and newborn screening and laboratory testing were expedited to assess his risk. He was healthy and did not experience symptoms of concern. In this case report, we emphasize the importance of close collaboration with maternal-fetal medicine team members during and immediately after pregnancy to ensure successful management of a female patient with OTC deficiency and her newborn.

Urea(lly) Got Me: An Uncommon Etiology of Peripartum Liver Failure

A 23-year-old woman presented 4 days postpartum for agitation and confusion, with initial evaluation consistent with acute fatty liver of pregnancy (AFLP). Later in her course, an amino acid panel was highly suggestive of citrullinemia type 1. She was started on arginine supplementation and glycerol phenylbutyrate and evaluated for a liver transplant. After starting the medication and diet modification, her liver failure resolved, and she was safely discharged. Urea cycle disorders may mimic AFLP with liver enzyme elevation, delirium, and hyperammonemia, but unlike AFLP, patients with urea cycle disorders will typically not recover without dietary modifications and/or medication.

ACER-001: a potential alternative to sodium and glycerol phenylbutyrate for treatment of urea cycle disorders

ACER-001: a potential alternative to sodium and glycerol phenylbutyrate for treatment of urea cycle disorders

Perceptions and use of phenylbutyrate metabolite testing in urea cycle disorders: Results of a clinician survey and analysis of a centralized testing database

The nitrogen scavengers sodium and glycerol phenylbutyrate (PB), approved for chronic treatment of urea cycle disorders (UCDs), undergo hepatic conversion to phenylacetate (PAA), which conjugates glutamine to form phenylacetylglutamine for urinary nitrogen excretion. Elevated PAA has been associated with reversible neurological toxicity, with symptoms similar to hyperammonemia. Plasma PB metabolite analysis can assess for toxicity and therapeutic drug levels. An online survey was undertaken to assess US clinician perceptions and use of the test in addition to an analysis of centralized US laboratory records. Survey responses from 52 clinicians were analyzed, including 58% who reported using plasma PB metabolite testing. Test users reported managing more UCD patients than nonusers. Users rated the test as “often helpful” for ruling out PAA toxicity (44%), informing PB dosing decisions (42%), and assessing adherence (28%). Test results were reported as most often unremarkable (61%) or suggestive of poor adherence (13%); 46% of users had never encountered results indicative of PAA toxicity. Analyses of laboratory records for 1668 plasma metabolite tests determined that only 5% of samples had plasma PAA-to-phenylacetylglutamine ratios associated with increased risk of PAA toxicity. Nearly half of surveyed clinicians were unsure of metabolite targets; those conducting ad hoc (versus regular) testing were significantly more likely to be unsure of targets. One-fifth of test users identified uncertainties, including questions about test validation, timing, and interpretation. Increased awareness of published PB metabolite data and further clinician education on test interpretation may help to inform the use of metabolite testing to optimize UCD care.

The burden of pharmacological treatment on health-related quality of life in people with a urea cycle disorder: a qualitative study

BackgroundUrea cycle disorders (UCD) are inborn errors of metabolism, typically presenting neonatally. Excess ammonia builds rapidly within the body risking hyperammonemic episodes and potentially death. Long-term management of the condition includes restrictive protein consumption, pharmacological interventions and, in extreme cases, liver transplantation. Pharmacological treatments such as sodium benzoate and sodium phenylbutyrate have proven effective but not without a multitude of negative attributes including poor taste, higher dosage and associated gastrointestinal discomfort that impacts health-related quality of life. Glycerol phenylbutyrate (GPB) has recently become a widely available pharmacological treatment with early reports of improved qualities, including taste and administration method. The following study aims to explore the burden of pharmacological treatment and the effects of the transition to GPB on health-related quality of life in people with a UCD.ResultsNine carers of children living with a UCD (mean age = 12.44, SD = 10.26) were interviewed regarding their experiences of pharmacological treatment in relation to their, and their child’s, health-related quality of life after transitioning to GPB. Three main themes were identified: psychological health, physical health and social participation. Carers struggled with anxiety surrounding their child’s condition and the battle of administering medication. Medication administration was perceived to have improved since the transition to GPB, alleviating distress for both carer and child. Issues involving school were described, ranging from difficulties integrating their child into mainstream schooling and the impact of treatment on participation in school and extracurricular activities. Carers encountered issues sourcing syringes to administer GPB, which induced stress. It could be suggested that some burden had been relieved by the transition to GPB. However, it appeared that difficulties associated with the illness would persist despite treatment, owing to the continuing nature of the condition.ConclusionsAdhering to a strict pharmacological regime caused immense stress for both carers and children, severely impacting on typical social activities such as eating at a restaurant or going on holiday. GPB was perceived to have alleviated some burden in terms of administration given improved characteristics concerning taste and dosage, important characteristics for both carers and children living with UCD. Practitioners should consider these findings when making clinical decisions for children with UCD and the effect of pharmacological treatment on carer’s health-related quality of life. Outreach work to facilitate greater understanding of the condition should be conducted with key locations, such as children’s schools. This would also help to alleviate carer burden.

Hepatic Manifestations of Urea Cycle Disorders.

Content available: Author Interview and Audio Recording.

Exposures of Phenylacetic Acid and Phenylacetylglutamine Across Different Subpopulations and Correlation with Adverse Events.

BackgroundElevated plasma ammonia is central to the pathogenesis of hepatic encephalopathy. Sodium phenylacetate or glycerol phenylbutyrate is approved for urea cycle disorders, but limited clinical data are available for hepatic encephalopathy. Phenylacetic acid (PAA) plasma exposure has been reported to correlate with neurologic adverse events in patients with cancer but not in patients with urea cycle disorders or hepatic encephalopathy. Ornithine phenylacetate, an intravenous dosage form of the l-ornithine salt of phenylacetate, is under development for hepatic encephalopathy.ObjectiveThis analysis summarized the pharmacokinetics and safety of ornithine phenylacetate to support the dosing strategy and to assist with the monitoring and management of neurologic adverse events in a global clinical development program.MethodsPhenylacetic acid and phenylacetylglutamine (PAGN) pharmacokinetic data and adverse events from five clinical studies were included in the analysis. Hepatic and renal dysfunction were assessed by baseline Child–Pugh score and creatinine clearance, respectively. Predicted plasma exposures of PAA at the occurrence of neurologic adverse events were used for exposures and neurologic adverse event analysis.ResultsPhenylacetic acid exhibited nonlinear pharmacokinetics. Phenylacetic acid exposure was 35% higher in Child–Pugh C than in Child–Pugh B. No significant pharmacokinetic difference was identified between Caucasian and Asian subjects after body weight adjustment. Phenylacetylglutamine renal clearance decreased by five-fold in severe renal impairment compared with subjects with normal renal function. Renal dysfunction significantly elevated PAGN plasma concentrations; however, elevated PAGN due to reduced excretion of PAGN did not change PAA exposure and plasma ammonia levels. No correlation was observed between PAA plasma exposure and neurologic adverse events in patients with stable cirrhosis or acute hepatic encephalopathy.ConclusionsDose adjustment should be considered for patients with low body weight and severely impaired hepatic function. Phenylacetic acid plasma exposure was not correlated with neurologic adverse events in the ornithine phenylacetate target patient population.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40262-021-01047-5.

Ammonia Removal by Metabolic Scavengers for the Prevention and Treatment of Hepatic Encephalopathy in Cirrhosis.

Effective lowering of circulating ammonia is the mainstay strategy in the prevention and treatment of hepatic encephalopathy in cirrhosis and there is increasing interest in agents with the metabolic potential for the active removal of ammonia by the liver and skeletal muscle by agents including l-ornithine l-aspartate, branched-chain amino acids, as well as the re-purposing of benzoate and phenylacetate currently employed for the control of hyperammonaemia in congenital urea-cycle enzymopathies. Based upon results of multiple systematic reviews with meta-analyses, l-ornithine l-aspartate demonstrably lowers circulating ammonia in patients with cirrhosis with concomitantly improved mental status. Distinct mechanisms responsible include optimisation of hepatic metabolic pathways for ammonia removal as well as direct hepatoprotective effects involving the release of glutathione and of nitric oxide with beneficial effects on hepatic microcirculation. l-ornithine l-aspartate also prevents cirrhosis-related sarcopenia, leading to increased capacity for ammonia removal by skeletal muscle. Branched-chain amino acids continue to be prescribed as nutritional supplements with the potential to result in improvements in liver function. Sodium benzoate, glycerol phenylbutyrate and an analogous compound l-ornithine phenylacetate were also evaluated. Glycerol phenylbutyrate was the only agent with a beneficial effect on both hyperammonaemia and hepatic encephalopathy. None were superior to lactulose for the lowering of blood ammonia.

Glycerol phenylbutyrate efficacy and safety from an open label study in pediatric patients under 2 months of age with urea cycle disorders

Background/AimsNeonatal onset Urea cycle disorders (UCDs) can be life threatening with severe hyperammonemia and poor neurological outcomes. Glycerol phenylbutyrate (GPB) is safe and effective in reducing ammonia levels in patients with UCD above 2 months of age. This study assesses safety, ammonia control and pharmacokinetics (PK) of GPB in UCD patients below 2 months of age. MethodsThis was an open-label study in UCD patients aged 0 – 2 months, consisting of an initiation/transition period (1 – 4 days) to GPB, followed by a safety extension period (6 months to 2 years). Patients presenting with a hyperammonemic crisis (HAC) did not initiate GPB until blood ammonia levels decreased to below 100 µmol/L while receiving sodium phenylacetate/sodium benzoate and/or hemodialysis. Ammonia levels, PK analytes and safety were evaluated during transition and monthly during the safety extension for 6 months and every 3 months thereafter. ResultsAll 16 patients with UCD (median age 0.48 months, range 0.1 to 2.0 months) successfully transitioned to GPB within 3 days. Average plasma ammonia level excluding HAC was 94.3 µmol/L at baseline and 50.4 µmol/L at the end of the transition period (p = 0.21). No patient had a HAC during the transition period. During the safety extension, the majority of patients had controlled ammonia levels, with mean plasma ammonia levels lower during GPB treatment than baseline. Mean glutamine levels remained within normal limits throughout the study. PK analyses indicate that UCD patients <2 months are able to hydrolyze GPB with subsequent absorption of phenylbutyric acid (PBA), metabolism to phenylacetic acid (PAA) and conjugation with glutamine. Plasma concentrations of PBA, PAA, and phenylacetylglutamine (PAGN) were stable during the safety extension phase and mean plasma phenylacetic acid: phenylacetylglutamine ratio remained below 2.5 suggesting no accumulation of GPB. All patients reported at least 1 treatment emergent adverse event with gastroesophageal reflux disease, vomiting, hyperammonemia, diaper dermatitis (37.5% each), diarrhea, upper respiratory tract infection and rash (31.3% each) being the most frequently reported. ConclusionsThis study supports safety and efficacy of GPB in UCD patients aged 0 -2 months who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. GPB undergoes intestinal hydrolysis with no accumulation in this population.

S2682 CTLN1 as a Mimic of AFLP: Post-Partum Liver Failure as Index Presentation of a Urea Cycle Disorder

INTRODUCTION: Pregnancy physiology creates a unique differential for liver disease to include urea cycle disorders (UCD) and acute fatty liver of pregnancy (AFLP) in addition to other common diseases. UCD typically present in neonates (1 in 35,000 births) yet can affect adults during periods of high catabolic stress. Little is known about the onset of liver disease in UCDs as presentations range from no symptoms to acute liver failure (ALF). AFLP is an obstetric emergency and can rarely present post-partum. Due to significant overlap in clinical presentation, the Swansea criteria for AFLP may not adequately discriminate between AFLP and UCD. We present a 23 year old female with ALF 4 days post-partum diagnosed with late-onset citrullinemia type I (CTLN1) while meeting clinical criteria for AFLP. CASE DESCRIPTION/METHODS: A 23 year old female presented 4 days postpartum with confusion, agitation and dilated pupils. Shortly after admission, she became unresponsive and was intubated. Initial labs suggested ALF: AST 86 U/L, ALT 96 U/L, albumin 2.6 g/dL, INR 2.2 and ammonia 149 umol/L. Head CT, MRI and toxicology studies were unremarkable. RUQ ultrasound showed hepatic steatosis and she met greater than 7 Swansea criteria for AFLP. She recovered with supportive care, though persistent serum ammonia and liver enzyme elevations prompted additional testing. Liver biopsy was non-specific with fibrosis. Serum citrulline was >1000 umol/l and low argininosuccinate suggested CTLN1. Genetic testing confirmed ASS1 compound heterozygosity. Arginine supplementation was started and she also received glycerol phenylbutyrate and transplant evaluation. With medication and diet modification, her labs normalized and she was discharged free of symptoms. DISCUSSION: CTLN1 typically presents in neonates and has an unpredictable presentation in late-onset disease. The liver is known to be affected yet there are few reports of a first presentation of CTLN1 with liver failure in adults. The diagnosis is challenging given the paucity of UCDs encountered in clinical practice. In addition, CTLN1 may mimic AFLP with liver enzyme elevation, delirium, hyperammonemia and steatosis on imaging. Treatment varies drastically between these entities as UCD requires dietary modifications and medication whereas AFLP requires immediate delivery or supportive care post-partum. Distinguishing between these diseases can be potentially lifesaving. We strongly recommend that UCDs be considered with amino acid testing in patients meeting criteria for AFLP.Figure 1.: Apoptotic bodies and lymphohistiocytic inflammation in the lobules (H&E stain, 400x).